The Evolution of Meiosis From Mitosis

Anecdotal, Historical and Critical Commentaries on Genetics Edited by James F. Crow and William F. Dove … if there is one event in the whole evolutionary sequence at which my own mind lets my awe still overcome my instinct to analyse, and where I might concede that there may be a difficulty in seeing a Darwinian gradualism hold sway throughout almost all, it is this event—the initiation of meiosis. W. J. Hamilton (1999, p. 419) THE origins of meiosis in early eukaryotic history have never been satisfactorily explained. Since the reduction-division process in meiosis is essential for sexual life cycles, discussion of the origins of meiosis has been closely tied to debates about the evolutionary value of sex itself and the selective pressures for its maintenance. Yet the cytological events involved in the origins of meiosis are as puzzling as the question of selective pressures. While meiosis almost certainly evolved from mitosis, it has not one but four novel steps: the pairing of homologous chromosomes, the occurrence of extensive recombination between non-sister chromatids during pairing, the suppression of sister-chromatid separation during the first meiotic division, and the absence of chromosome replication during the second meiotic division. This complexity presents a challenge to any Darwinian explanation of meiotic origins. While the simultaneous creation of these new features in one step seems impossible, their step-by-step acquisition via selection of separate mutations seems highly problematic, given that the entire sequence is required for reliable production of haploid chromosome sets. Both Maynard Smith (1978) and Hamilton (1999) regarded the origins of meiosis as one of the most difficult evolutionary problems. In this Perspectives article, we present a hypothesis of the origins of meiosis that encompasses both the cytological novelties and the selective forces that might have favored them. We first present the reasons for thinking that the initial step involved a key innovation, that of extensive homolog pairing (synapsis), and then discuss how the other three distinctive properties can be accounted for. We next ask what selective pressures might have favored the acquisition of homolog synapsis. The conclusion is surprising: the initial function of chromosome pairing was to limit, not enhance, recombination. Finally, we review the evidence that much of the molecular machinery required for the initial forms of homolog pairing probably existed in proto-eukaryote unicellular forms prior to the evolution of meiosis and therefore could have been readily “recruited” for the new role. Some experimental tests of the hypothesis are proposed. In the evolution of the eukaryotes, it can be assumed that the earliest eukaryotic species were single-cell haploid forms, possessing just a single set of chromosomes, and that they propagated by mitosis. While many of the simplest contemporary eukaryotes, namely protists and fungi, exhibit the mitotic propagation of both haploid and diploid states, diploidy is almost certainly a derived state. In principle, the very first diploid cells could have first arisen either by cell fusion or by endomitosis. Hurst and Nurse (1991) have argued that the first diploids probably arose via rare endomitotic errors rather than by cell fusion. Yet, since non-sexual cell and nuclear fusions can occur independently of sex (“parasexuality”), either route to early diploid states is possible. In this view, the formation of occasional diploid cells predated regular sexual life cycles in eukaryotes. The origins of mitosis itself in the first eukaryotes are, of course, of high interest. The fact that mitosis is a universal eukaryotic property suggests that it arose at the base of the eukaryotic tree. A key point is that there are prokaryotic homologs of all the key molecules employed in eukaryotic mitosis (see reviews by Hirano 2005 and Erickson 2007). These include the actins, required for daughter cell separation in eukaryotes; the tubulins, required in eukaryotes for the mitotic spindle and movement of chromosomes; and the molecules required for chromosome condensation and sister-chromatid cohesion, members of the so-called structural maintenance of chromosomes (SMC) family. The prokaryotic members of the tubulin family are the FtsZ genes, which were first discovered in Escherichia coli but later found in many prokaryotic species, while similarly, the homologs of the SMC proteins are found throughout the eubacterial and archaebacterial kingdoms. It is not difficult to imagine that members of the actin-related, FtsZ, and SMC gene families could have been evolutionarily recruited for use in the first primitive forms of mitosis; the latter must have involved a switch from membrane-based to spindle-based attachment points for segregating sister chromosomes. The evolution of meiosis, however, poses problems of a different order. The crucial but reasonable deduction, based on both cytology and genetics, is that meiosis evolved from mitosis (Cavalier-Smith 1981; Simchen and Hugerat 1993). While the various similarities between the two forms of cell division argue for a close evolutionary relationship between them, the greater complexity of meiosis indicates that it is the derived process. Furthermore, while mitosis is universal in eukaryotic species, meiosis is merely ubiquitous, consistent with its loss in some eukaryotic lineages. Comparative evidence suggests that meiosis appeared early in eukaryotic cell history (Ramesh et al. 2005; Schurko and Logsdon 2008), and its high degree of similarity in different taxonomic groups suggests that it arose only once (Hamilton 1999; Ramesh et al. 2005). As noted above and summarized in Table 1, the cytological events specific to meiosis are the following: (1) the acquisition of homolog pairing (and its concomitant, homolog separation), (2) the occurrence of efficient intergenic recombination between homologs during pairing, (3) the suppression of sister-chromatid separation in the first division, and (4) the absence of S phase at the start of the second division. Comparison of mitotic and meiotic stages The four novel properties of meiosis are indicated by italics. Comparison of mitotic and meiotic stages The four novel properties of meiosis are indicated by italics. Most of the attention of evolutionary geneticists has focused on the second step—extensive genetic recombination during pairing—and its significance as a generator of genetic diversity (Fisher 1930; Muller 1932; Maynard Smith 1978; Crow 1988). Yet, while genetic recombination is a key feature of meiosis, it is not unique to this process. Recombinational capacity is found throughout the prokaryotes and therefore must considerably predate eukaryotes and, therefore, meiosis (Levin 1988; Cavalier-Smith 2002; Marcon and Moens 2005). Accordingly, the original proto-eukaryote cells must also have possessed the enzymatic machinery for recombination. In particular, a crucial set of molecules for genetic recombination, the recA family of proteins, is utilized for recombination in both prokaryotes and eukaryotes (Aboussekhra et al. 1992; Shinohara et al. 1992). Furthermore, within eukaryotes, genetic recombination is not restricted to meiosis. Diploid somatic cells of fungi, plants, and animals undergo chromosomal crossing over, the phenomenon known as “mitotic recombination.” There are, however, three significant contrasts between meiotic and mitotic recombination. First, mitotic recombination between homologs takes place at a very much lower frequency than in meiosis. Second, while crossing over between sister chromatids in mitotic cells is fairly frequent (as seen with physical labeling techniques), meiosis is structured to promote crossing over between non-sister chromatids. Third, as found in yeast cells, mitotic recombination is mediated efficiently by either of two recA homologs, rad51 and Dmc1, while meiotic exchange between homologs requires Dmc1 specifically (reviewed in Neale and Keeney 2006). If mitosis preceded meiosis in evolution, it seems equally likely that mitotic recombination preceded meiotic recombination. In thinking about the origins of meiosis, a point of interest is that meiosis as it exists is not the simplest conceivable process for producing haploid cells from diploid cells. In principle, premeiotic DNA replication would not be necessary. The unreplicated chromosomes would simply pair with each other with or without recombination and would move to opposite poles to produce just two haploid nuclei. The whole process would be accomplished in one division, not two. This hypothetical sequence of events, “one-step meiosis” (Cavalier-Smith 1981; Archetti 2004), differs from the normal “two-step” meiosis in involving (1) the active suppression of DNA synthesis and (2) the pairing of homologous but unreplicated chromosomes prior to metaphase. Although one-step meiosis would achieve the same results as actual meiosis, it is hard to imagine how both properties could have arisen readily and simultaneously from mitosis. In contrast, consider meiosis as it actually occurs. It with S which may in features from the normal mitotic S phase and chromosomes that each of a pair of sister chromatids. This is by pairing of homologous chromosomes their entire (synapsis), a that is in most eukaryotic species as the chromosomes In this homologous non-sister chromatids with each only but at their recombination, the chromosomes and the homologs on the There are two to which the chromatids are in to mitosis, the not in this first meiotic the homologs simply separate to opposite This absence of in the first meiotic division a in the molecular of a of the of sister-chromatid homologs are In to the of sister chromatids to opposite poles in mitosis, both sister chromatids of each chromosome in I are to spindle to the same (reviewed in and the two of chromosomes by are within they are these are in the of the of the mitotic The absence of replication in the second meiotic division from the same that of replication in the phase of cells for mitosis, namely the absence of of one or of the the at replication origins their during S phase (reviewed in and 2005). Although the is not it seems likely that sister-chromatid separation at the a that the process of In the absence of that molecular at the of meiosis the chromatids undergo a new of the is that a second S of meiosis simply of chromosome in is by and then by in which the sister chromatids are and to opposite two haploid with single chromatids. The separation of sister chromatids in meiosis molecular and to involved in sister-chromatid separation in mitosis (reviewed in and 2006). the second division a of from each initial meiotic I and each of these daughter one unreplicated and the evolution of meiosis requires new events than the one-step process. it actually only namely the of homologous chromosomes, each of two sister with the of the sequence in the known of mitosis for chromosomes. Archetti has which is based on of selection as to the hypothetical of one-step meiosis is a if it exists at In contrast, is based on the known of cytology and molecular key therefore, is that the of meiosis involved the evolution of and the of this step the mitotic pairing at first might to be a Yet, pairing of homologs in somatic cells has been found both in and in yeast et al. somatic pairing differs from meiotic in three (1) it is not as extensive (2) it not to the of genetic recombination seen in and (3) it in either or each chromosome to to the independently of its if homolog pairing in mitotic cells is eukaryotic then the origins of meiotic have involved only its and or extensive of homologs, at the would be a of not a novel As argued the absence of sister-chromatid separation at the of meiosis I would the of homolog are while the absence of S phase in meiosis would be a of the absence of sister-chromatid The distinctive feature of meiosis, namely high recombination during chromosome pairing, can be seen as a property that evolved later (see that a key a mitotic a meiotic one is not the first of its Cavalier-Smith argued that suppression of in was the key in meiosis. This however, homolog pairing, which is a Furthermore, as noted the absence of the in sister-chromatid with to the poles between and and in the in attachment between and chromosomes at the of chromosomes and In Table we the stages of mitosis and meiosis in of of key meiotic stages to mitotic stages DNA during almost certainly of later meiotic the that it is chromosomes that are first at then at In that the chromosomes are and to The are the the only is in the of chromosomes to mitosis. of key meiotic stages to mitotic stages DNA during almost certainly of later meiotic the that it is chromosomes that are first at then at In that the chromosomes are and to The are the the only is in the of chromosomes to mitosis. The conclusion that with the of homolog the mitotic two The first the of the selective pressures for this new chromosomal and the second the molecular for this novel cytological In this we discuss the selective in the molecular of the we the molecular A feature of contemporary meiosis is its with high of intergenic recombination. The selective are recombination gene and new most thinking about the evolution of meiosis has focused on the selection pressures to the of gene and to promote (Fisher 1930; Muller 1932; Maynard Smith 1978; 1988). this any selection for homolog would actually have involved selection for of genetic recombination mediated by the that the of intergenic recombination were a selective for the origins of meiosis has been Although the are in of the to (see review by the explanation of selection with to for the Yet selection with initial chromosome pairing in may have they would have to have been than the of intergenic recombination. is that the initial of meiosis was of DNA via recombination et al. 1988). The for efficient DNA is a and of cells, as by its prokaryotic cells, and to early cells from and other as as Furthermore, recombination of homologous efficient of DNA In coli cells, for of either of the key recombination recA or the to the of other DNA Smith The for DNA as the of meiosis that the forms of DNA were for the of the earliest eukaryotic cells. however, are with a of DNA (Levin 1988; Cavalier-Smith 2002; Marcon and Moens and the of prokaryotic life in the of eukaryotic cells suggests that DNA must have to with the of DNA with that in of to and the highly efficient of sister chromatids in mitotic cells et al. 2008), the that meiosis was for capacity not however, the two about selection pressures for meiosis are then explanation is If the that homolog was the key initial event in the of meiosis, one has to ask just what pairing The is and that may be the key to the promote not only recombination but also recombination between We in that homolog was it of recombination, the of pairing and recombination. homolog pairing would to that only homologous at different chromosomal would As in the DNA the selective would be but the would be of the of DNA (as in the DNA the selective of the new process would be the of is to the that recombination, in cells, can have and is to et al. 1988). There in some experimental evidence for this et al. extensive of DNA in a gene that they in the The of these however, is than a The (1) cells, (2) of mitotic recombination, (3) meiosis in between with formation of and meiotic and (4) in diploid but not in haploid This is most simply as in the or of recombination in both mitosis and meiosis. The of diploid is probably to genetic events by recombination and to In the recombination in and to to errors in of the genetic are to of is by The recA homolog in the is present at a of but of the cells to either or and its to in the highly This suggests that the of the recA rather than homolog pairing, can be the for recombination. A that the that recombination has to be to from by the results of many that recombination frequency of DNA as a function of that there is in with of (see in 2005). a is the of a process that has to be in If one of the of recombination is the then the greater the nuclear of the greater the of errors pairing chromosome by occur at in the et al. It is that and a key feature of eukaryotic evolution (Cavalier-Smith would have the for recombination events between at different chromosomal The would include and in recombination and and chromosomes from the of would be to as a function of the in throughout the would the of and the of cells in any In contrast, homolog prior to recombination this of It not Recombinational errors occur in meiosis, between homologous as first by the phenomenon of the and mutations in The of in and et al. et al. 2005; et al. et al. has just how recombination errors are, with pairing of homologs in meiosis. The key however, is in the absence of extensive pairing, errors place the of the which has pairing on the seems to have a of and as a of errors between its own et al. et al. within a haploid derived from the species undergo exchange between but than in the et al. 2007). A reasonable from all is in early eukaryotic cell evolution, any via the of new would have the frequency of errors between There is a second however, in which recombination, prior to the of meiosis, might have been that recombination in a diploid cell can place at any point in the cell but that of recombination events is not recombination events at the of chromosome separation in would produce chromosome to either chromosome or The the and the greater the of chromosomes, the greater the of It has been in coli that recombination events can chromosome to the production of cells et al. In contemporary eukaryotic cells, events are the use of DNA which chromosome is cells, however, might have just as contemporary prokaryotic cells to and might have been to chromosome Diploid cells in early eukaryotes would have a would have required efficient for but would have to the of namely errors between or events at the of mitosis. of events or process could have these cells to between the of DNA and the of process that both DNA sequence and recombination to a prior to the separation of chromosomes would to this This is what meiotic pairing of homologs pairing promote the of or that a DNA would the same of recombination events to a that chromosome as in homolog would promote the maintenance of the of chromosomal events and the of we that the selection pressures for homolog and the origins of meiosis were to and to it to a while its A cell that evolved this for diploid cells would be in its genetic mutations could have that recombination during the chromosome pairing and this as seen in normal mitotic cells. the reduction-division the haploid would have In the initial sequence of events not have involved the of sex cells but a as if the of meiotic origins is to the evolution of homolog the molecular of that process The molecular and cytological complexity of the pairing process in species at first seems to the of via one or two the evolution of from a et al. was a crucial features as and the for recombination to promote normal chromosome could have evolved pairing in diploid cells, just one or two homolog might have involved and In principle, the molecular evolution of a new that specifically homolog pairing might have the crucial for meiosis. In contemporary yeast cells, the is specifically at and the during normal of homologs and is essential for its absence to the loss of division and the occurrence of sister-chromatid separation in and Nurse 1999; and it is that homolog was by of chromosome and mediated by homologous sequence and by Although of homologs not in all contemporary and and might not have been involved in the earliest forms of in with a of chromosomes, recombination in principle, have to homolog the for the origins of the for and recombination might have these to at other in one Although the origins of homolog can never be known with it is how much of the molecular machinery that it is between prokaryotes and eukaryotes and between mitosis and meiosis. In particular, the of recombination and their in eukaryotes at the of during meiosis et al. is evidence of the evolutionary between prokaryotic and eukaryotic recombination. The molecular evolution of Dmc1 was a key step in recombination, but as a of the recA gene its origins are not a of the SMC family proteins, in the and the in sister-chromatid in both meiosis and mitosis (reviewed in and Finally, as noted the molecular machinery for is between mitosis and meiosis These molecules include a and one of its the (reviewed in and 2006). In it that most of the molecular required for the evolution of homolog pairing and recombination between homologs were present in one or in the earliest premeiotic cells. The discussion has one crucial the fact that meiosis is to sexual cycles of sexual would be without the division that takes place in meiosis. however, the evolutionary of homolog pairing to events that may have independently of fusion. events, by recombination and division to haploid states, are sexual cycles were first in and cycles the but they are also known in the and in cells where the of is from to diploidy et al. 2005). We therefore, that homolog and the of diploid states in some of in the early proto-eukaryote and that the relationship between via and meiosis was a evolutionary In this view, some of and division of some to a lower without a meiosis in The of evolutionary between early events (and their and meiosis is consistent with the fact and meiosis can be In many unicellular eukaryotes, haploid fusion to nuclear which meiosis, the haploid state. In contrast, in eukaryotes, meiosis is the initial fusion of sex cells, place much later in the life during different in different the of meiosis and the employed the evolutionary The presents a of the by the difficulty of for the simultaneous origins of sex and meiosis in In some of division could have preceded both meiosis and the first of in early eukaryotes, as also by Hurst and Nurse There of course, to the hypothesis since the cells in which meiosis first existed over and this the hypothesis two experimental The first is if extensive homolog pairing could be in the of diploid mitotic cells, it could a sequence of two cell In principle, this might be in yeast cells by the of and Dmc1 A would for the A however, would be given the that cells have evolved properties that the original The second is that high recombination in either diploid mitotic cells or events in meiotic cells promote with in cell Furthermore, the of events as a function of the of chromosomes haploid the and the of recombination events In particular, it be to diploid and yeast with rad51 Dmc1 this one could then of these in various stages of the mitotic cell or in meiosis The is that or be and that have than In yeast in their DNA recombination events in somatic cells to chromosomal or chromosomal It is however, that of recombination would be to recombination events, the results of and In this very a of chromosome be either by very or by The latter have been to to sister-chromatid pairing in diploid yeast cells et al. a sister-chromatid et al. et al. 2007). hypothesis that produce and various in yeast than in diploid of this would the that there were selection pressures to recombination and promote the of recombination. The evolutionary origins of meiosis have been a of for and are to the about the value of sexual which from the 1988). Yet the in this has been on the of the selection pressures rather than on the actual cytological Furthermore, much of the discussion has been about the maintenance of sex (and rather than its in animals Smith 1978; Hamilton 1999; and 2004), a of that arose meiosis the origins of meiosis, one must consider the earliest cells and their Marcon and Moens 2005; 2006). we have argued that the origins of meiosis from mitosis involved only one new namely homolog synapsis. of the other features of meiosis are in mitosis and would have been as of the features of mitosis while the one could have evolved We that the selective pressures for extensive homolog pairing capacity in early eukaryotes were to and recombination, recombination and and and would also have probably simultaneously genetic recombination but the A conclusion from a of cells has been by of the molecular machinery for the evolution of meiosis from mitosis suggests that much of it could have been recruited for use in meiosis via point features of meiosis, as and the for recombination to chromosome would have been evolved A of evolutionary is in of which is as a of events in the evolution of meiosis. events or while the for the process indicates and hypothesis in the that meiosis to promote intergenic recombination, new for selection to one of has that the of intergenic recombination were in the early of eukaryotic cells for with prokaryotic cells 2006). We argue however, that this of meiosis not the initial selective for its origins. Although differs from thinking about the of meiosis, it is consistent with the known and its recombination has to be in to the of the of the genetic We James F. and William for their on early of this and and two for on the original We are also to and for to the results of et al. and the of